Fiber-based nano drug delivery systems (NDDS)

ABSTRACT

A drug delivery system in the form of homo-component, bi-component or multi-component fibers wherein one of more of the components comprise a drug compounded with a polymer carrier. These fibers are packed to form a tablet directly, or are chopped and placed in a capsule.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to the U.S. provisionalpatent application Serial No. 60/334,517, filed Oct. 31, 2001, andentitled “Drug Delivery System/Extruded Fiber,” which application isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to processes for creating extrudedfibers containing a mixture of drugs and pharmaceutically acceptablepolymers such that the drugs form nanofibers. The nanofibers of thepresent invention provide significant surface area allowing fastdissolution of the drugs. Means for directly forming such fibers intocaplets or tablets are also an aspect of this invention.

BACKGROUND ART

[0003] The solubility behavior of a drug is a key determinant of itsbioavailability. Solubility presents a challenge to the development of asuitable formulation for drugs. With the recent advent of highthroughput screening of potential therapeutic agents, the number ofpoorly soluble drug candidates has risen sharply and the formulation ofpoorly soluble compounds now presents one of the most frequent andgreatest challenges to formulation scientists in the pharmaceuticalindustry.

[0004] The production of drug delivery systems by melt extrusion of apolymer/active ingredient mixture is known in the art. In general, suchprocesses Examples of such drug delivery systems are generally describedin the U.S. patents set forth in Table 1. TABLE 1 U.S. Pat. No. TitleYear U.S. Pat. No. 5456923 Method of manufacturing solid dispersion 1995U.S. Pat. No. 5665369 Fast-dispensing solid PVP-containing crop 1997protection formulation and process U.S. Pat. No. 5939099 Solid activeextrusion compound prepara- 1999 tions containing low-substitutedhydroxy- propylcellulose U.S. Pat. No. 5958452 Extruded orallyadministrable opioid formulations 1999 U.S. Pat. No. 6051253 Productionof solid drug forms 2000 U.S. Pat. No. 6120802 Method of producingmulti-layer medica- 2000 ments in solid form for oral or rectaladministration

[0005] In general, the basic ingredients of a drug delivery systemcomprise (1) one or more pharmaceutically active ingredients (polymers);(2) one or more polymer binders; and (3) pharmaceutically acceptableancillaries, plasticizers, and the like. Generally, active ingredientsdo not decompose at extrusion temperatures. Pharmaceutical auxiliariesmay include plasticizers, fillers, lubricants, flow regulators,colorant, stabilizers, and the like, and are typically not affected bythe process conditions. However, polymer carrier or binder componentsare preferably thermally stable so that they are not decomposed atextrusion temperatures. If such carriers or binder components aremelt-extruded, they are preferably thermoplastic. In general, theformulation of the polymer or the polymer mixture controls the activeingredient profile required by the end user. Examples of themanipulation of polymer carriers to control active ingredient profilesand release rates are set forth in, e.g., U.S. Pat. No. 5,665,369 toWedlock (crop protection formulation, where rapid release is critical;PVP is used as a polymer binder); U.S. Pat. No. 5,939,099 to Grabowski(mixture of thermoplastic water soluble polymer and water insoluble,swellable, non-thermoplastic polymer L-HPC used to control the activeingredient release rate; and U.S. Pat. No. 5,958,452 to Oshlack (mixtureof hydrophobic polymer and hydrophobic fusible carrier used in an orallyadministrable opioid formulation, where hydrophobic fusible carrierslows down the release of the active agents).

[0006] In general, the process for creating drug delivery systems towhich the present invention relate comprises (1) a preparation step,wherein the ingredients of the drug mixture are mixed and melting orsoftened; (2) an extrusion step and, optionally, a (3) cooling orshaping step.

[0007] During the first preparation step, a common challenge isobtaining a homogeneous dispersion of the active ingredients in polymerbinders. U.S. Pat. No. 5,456,592 to Nakamichi et al. describes the useof a twin-screw extruder to improve the process to obtain soliddispersion. “Solid dispersion” or “solid solution” generally refers to amixture in which the active ingredient is present in the form of amolecular dispersion in the polymer. The twin-screw extruder consists ofa metering feeder unit, a barrel, screws, exit dies, etc. Such extrudersenhance the mixing process by creating high shear forces, transportcapacity and compounding effects. Hence, the production of a soliddispersion can be obtained at lower temperature allowing the use ofthermally sensitive ingredients. In addition, such extruders generatelower heats of friction than single screw extruders.

[0008] After preparation, drug mixtures are extruded through a suitabledie. The mixture is melted or softened at the extrusion temperature. Theshape of the die depends on the desired shape of drug formulation.Coextrusion dies may be used for multiple-layer drug production as setforth in U.S. Pat. No. 6,120,802 to Breitenbach.

[0009] The extruded drug mixture strand is solidified by cooling. Thesolid drug can be formed through a shaping process before or after thecomponents are solidified. After cooling, the strand can be cut ordivided into multiparticulates of desired size and divided into unitdoses (see, e.g., U.S. Pat. No. 5,939,099). U.S. Pat. No. 6,051,253 toZettler describes direct solid drug formation by splitting a drugmixture strand and then rounding-off the end of the strand before theextrudate is solidified. U.S. Pat. No. 6,120,802 to Breitenbachdescribes a one-step direct shaping process such that the extrudate iscut into the final tablet shape immediately after the extrusion, withthe cutter/shaper being located downstream of the extruder die.

SUMMARY OF THE INVENTION

[0010] The following equation, based on the Noyes-Whitney equation,provides a general guideline as to how the dissolution rate of poorlysoluble compounds may be improved:$\text{Rate~~of~~dissolution} = {\frac{C}{t} = \frac{{AD}\left( {C_{s} - C} \right)}{h}}$

[0011] A=Surface Area

[0012] D=Diffusion Coefficient of the compound

[0013] C=Contentration of the drug at time t

[0014] h=Thickness of diffusion boundary layer

[0015] According to this analysis, dissolution can be improved byincreasing the surface area available for dissolution by decreasing theparticle size of the solid compound and/or by optimizing the wettingcharacteristics of the compound surface, to decrease the boundary layerthickness, to ensure sink conditions for dissolution and to improve theapparent solubility of the drug under physiologically relevantconditions. This analysis provides a basis for this invention.

[0016] The present invention relates to the development of an extrudedfiber-based nano drug delivery system (NDDS) by employing the extrusionof either a homocomponent fiber wherein the drug is mixed into thepolymer carrier, or a bicomponent fiber wherein the drug is in one orboth components, or a multi-component fiber wherein the drug and thecarriers may be in one or more of the components. The bicomponent andmulti-component fiber morphology allows the creation of very smallextruded fibers with fiber diameters of less than 500 nanometers. Inparticular embodiments, one or more of the components is the active drugcompounded together with a polymer carrier. One of the components may bea pharmaceutically acceptable polymer and may be the same as the polymerused for compounding the drug; alternatively, the polymer may bedifferent than one used for compounding the drug.

[0017] In other aspects, the present invention relates to processes forthe formation of tablets or caplets using extruded nanofibers.

DESCRIPTION OF THE DRAWINGS

[0018] Some of the objects of the invention having been stated otherobjects will become apparent with reference to the detailed descriptionand the drawings as described hereinbelow.

[0019]FIG. 1 is a schematic of a homo-component fiber spinning system.Preferably and typically, these fibers are larger than one micron.

[0020]FIG. 2 is a schematic of a bicomponent fiber spinning system.Preferably and typically, these fibers are can be smaller than onemicron;

[0021]FIG. 3 is a schematic of a meltblowing process that may be used inone embodiment of the invention. The fibers illustrated herein may beless than 0.5 micron.

[0022]FIG. 4 is a schematic of homo-component fibers with high surfacearea that may be used in embodiments of the present invention.

[0023]FIG. 5 is a schematic illustrating bicomponent fiber morphologiesthat may be used in the present invention.

[0024]FIG. 6 is an example of an NDDS of the present invention having astacked ribbon morphology.

[0025]FIG. 7 is an example of an NDDS of the present invention having aribbon morphology.

[0026]FIG. 8 is an example of an NDDS of the present invention having ahollow, sheath-core morphology.

[0027]FIG. 9 is an example of an NDDS of the present invention having atipped, trilobal morphology.

[0028]FIG. 10 is an example of an NDDS having a solid, sheath-coremorphology.

[0029]FIG. 11 is an example of a NDDS by using a solid,islands-in-the-sea morphology.

[0030]FIG. 12 is an example of a NDDS by using a hollow,islands-in-the-sea morphology.

[0031]FIG. 13 is an example of a NDDS having two different polymers inthe sheath and the core, wherein the drug has been added to both. Thedrug is available in the stomach and continues to be available forlonger periods when it reaches the lower intestines if the pHsensitivity of the polymers and in the sheath and the core are carefullyselected. These structures allow the formation of a long lasting drugwhere a single doze per day may be possible;

[0032]FIG. 14 is the schematic of a process for direct formation ofcaplets or capsules.

[0033]FIG. 15 is the schematic of a process for direct formation oftablets.

[0034]FIG. 16 is the schematic of a process for direct formation oftablets.

[0035]FIG. 17 is the schematic of the process for direct formation oftablets by using a drum former.

DETAILED DESCRIPTION OF THE INVENTION

[0036] The invention is a fiber based nano drug delivery system. Thisinvention addresses the development of the process for an extrudedfiber-based nano drug delivery system (NDDS) by employing ahomo-component, bi-component or multi-component fiber morphology whereinone or more of the components are the drug compounded together with apolymer carrier. Other components may be pure of compounded drug with apharmaceutically acceptable polymer. The latter may be the same as thepolymer used for compounding the drug or may be a different polymer.

[0037] The extrusion processes for homo-component and bicomponent fibersare shown in FIGS. 1 and 2 and the process for meltblowing is depictedin FIG. 3. The manufacturing of the fiber based nano drug deliverysystem (NDDS) however, is not limited to these processes. Spunbonding,flash spinning, solvent spinning and solution blowing are other possiblemethods for the manufacturing of the fibers for NDDS.

[0038] The present invention relates to fibers with enhanced surfaceareas in order to accommodate and facilitate faster dissolution of thedrug. In the present invention, the drug is included in a suitablepolymer carrier by compounding and/or blending, extruding the blended orcompounded material into fibers by extruding, thereby providing meansfor the delivery of the drug. The fibers will have enhanced areas inthat the fibers have a rough cross section, or have a fiber size tobelow one micron.

[0039]FIG. 4 illustrates one embodiment in which the solubility of ahomo-component fiber for NDDS is increased, and wherein the drug hasbeen compounded into the fiber forming polymer. These fibers may behollow, may have one or more holes and can be made by any of the wellknown extrusion processes.

[0040]FIG. 5 shows various possible bicomponent configurations of theinvention where the drug may be in one component.

[0041] FIGS. 6 to 13 show the possibilities and the sizes that can beachieved by means of bicomponent fiber spinning. Multi-component fiberspinning can also be employed to form similar structures of similardimension. In particular, FIG. 6 shows a stacked ribbon where thestructure is composed of alternate layers of the drug compound and thepure polymer. These can be stacked to have as many as 48 layers or more.The thickness for each layer can be as little as 200 nanometers or less.Because these layers are stacked, there will be little or no tendencyfor the fibers to deform and join at the ends. This structure can alsotake the form of a ribbon. FIG. 7 shows one such possibility where thelayers are in the form of a ribbon. A photomicrograph of a test specimenis also shown in FIG. 7 to the right of the fiber cross section.

[0042] A hollow sheath-core configuration is shown in FIG. 8.Alternatively, the drug may be at the tips of a trilobal fiber of thetype shown in FIG. 9. A solid sheath-core structure is shown in FIG. 10.When the drug carrying polymer is in the sheath, the dissolution ratewill be higher.

[0043] Segmented pie and hollow segmented pie configurations can lead tovery useful structures where each segment may be less than one micron tofacilitate dissolution. The segmented pie configuration is shown in FIG.11.

[0044] Smaller fibers can be achieved by using the islands in the seaconfiguration. The islands can be solid as shown in FIG. 12 or can behollow as shown in FIG. 13.

[0045] Longer lasting drug delivery systems can be created by aconfiguration such as the one shown in FIG. 14 where the sheath and thecore both contain drugs in a suitable polymer carrier. The carrierpolymers however, are different in their pH sensitivity or in theirdissolution rate.

[0046] The formation of tablets directly from the spun fibers ispossible by various means. The formation of capsules/caplets is possibleby directly cutting the spun fibers and encasing them in thecapsules/caplets as depicted in FIG. 15. Alternatively, the fibers canbe compressed to form a consolidated fibrous structure that can then becut and coated as shown in FIG. 16.

[0047] Another method for the manufacturing of the tablet directly fromthe extruded fibers is to collect these fibers in a drum former withcavities of the shape desired for the tablets. This is demonstrated inFIG. 17. The fibers will be dispensed into the cavities and compressedby means of a vacuum system. A hexagonal grid pattern will lead to theleast amount of waste.

[0048] Thus, the invention discovered is the process for making fiberscarrying a drug and forming tablet or caplets or capsules from the same.The fibers are formed such to maximize dissolution rates and thedelivery of the drug.

[0049] Further, the invention contemplates that the nanofibers can beformed to maximize the surface area of the fibers.

[0050] It will be understood that various details of the invention maybe changed without departing from the scope of the invention.Furthermore, the foregoing description is for the purpose ofillustration only, and not for the purpose of limitation—the inventionbeing defined by the claims.

What is claimed is:
 1. A fiber comprising polymers, binders and drugswhere the overall concentration of the drug can be between about 10%-90%by volume fraction and where fibers therein can have any cross sectionalshape.
 2. The fibers used in a drug delivery system according to claim 1wherein the fiber is homocomponent, bicomponent or multi-component. 3.The fiber used in a drug delivery system according to claim 1 whereinthe fiber is hollow.
 4. The fiber used in a drug delivery systemaccording to claim 1 wherein the fiber is multifilament or staple ofsmall denier (diameter<1 micron).
 5. The fiber used in a drug deliverysystem according to claim 1 wherein the fiber is monofilament of largedenier (diameter>1 micron).
 6. The fiber used in a drug delivery systemaccording to claim 1 wherein the fiber is selected from the groupconsisting of any biologically accepted polymer and any combinationsthereof.
 7. The fiber used in a drug delivery system according to claim1 wherein the fiber comprises a sheath/core cross-section, solid orhollow.
 8. The structure used in a drug delivery system wherein thefibers are formed into a ribbon or stacked configuration.
 9. The fiberused in a drug delivery system according to claim 1 wherein the fibercomprises a side by side cross-section.
 10. The fiber used in a drugdelivery system according to claim 1 wherein the fiber comprises anisland in the sea cross-section, solid or hollow.
 11. The fiber used ina drug delivery system according to claim 1 wherein the fiber comprisesa segmented pie cross-section, solid or hollow.
 12. The fiber used in adrug delivery system according to claim 1 wherein the fiber comprisesmore than 2 components.
 13. A method for forming a tablet from spunfiber comprising polymers, binders and drugs where the overallconcentration of a drug can be about 10% to 90% by volume fraction andwhere fibers therein can have any cross-sectional shape, the methodcomprising the steps of forming the tablets directly from spun fibers bydirectly cutting the spun fibers and then encasing them in the tablets.14. A method for forming a tablet from spun fiber comprising polymers,binders and drugs where the overall concentration of a drug can be about10% to 90% by volume fraction and where fibers therein can have anycross-sectional shape, the method comprising the steps of compressingthe spun fibers to form a consolidated fibrous structure and thencutting and coating the fibrous structure to form the tablets.
 15. Amethod for forming a tablet from spun fiber comprising polymers, bindersand drugs where the overall concentration of a drug can be about 10% to90% by volume fraction and where fibers therein can have anycross-sectional shape, the method comprising the steps of formingtablets directly from spun fibers by collecting the fibers in a drumroller having cavities therein of the shape desired for the tablets,compressing the fibers by means of a vacuum system, and coating thecompressed fibers to form the tablets.